Metronomic chemotherapy regimens using Microtubule-targeting agents: Mechanisms of action, preclinical activity and future developments

Abstract

Microtubule-targeting agents (MTAs) are amongst the most successful chemotherapeutic drugs commonly used in the clinic for the treatment of human cancers. Although originally administered at or close to the maximum tolerated dose once every 3 weeks, the discovery of their potent antiangiogenic properties at the end of the 1990s has led to the re-evaluation of treatment protocols. Nowadays, MTAs are often administered at lower doses either weekly or even more frequently following a metronomic schedule, thus leading to increased efficacy and decreased toxicity. In this chapter, we present an overview of the in vitro and in vivo studies that have contributed to the development of MTA-based metronomic chemotherapy protocols and increased our understanding of their mechanisms of action. First, we discuss the complex cellular and molecular mechanisms involved in the antiangiogenic activity of MTAs. We also present their effects on the immune system, which may contribute to the antitumour efficacy of MTA-based metronomic chemotherapy. Then, we review the results obtained with this type of therapeutic approach in preclinical models of human cancer, focusing on the most promising combination treatments. Finally, we oversee the future developments in this field in terms of new MTAs and novel formulations currently in development with the aims to improve efficacy and bioavailability while increasing tumour targeting and specificity.